The investigators propose to conduct a 2-arm, open-label pilot study to determine if early treatment with amitriptyline will decrease the frequency and severity of headaches after mild traumatic brain injury (TBI). Amitriptyline is a tricyclic antidepressant that is commonly available and inexpensive. It is used as a first-line drug for primary headache prevention in a very low dose range of 10-50 mg.

Specific Aim 1 is to conduct a 2-arm open-label study to examine the effect of preventive treatment with amitriptyline on the frequency and severity of headache after mild TBI.

Specific Aim 2 is to collect data needed for design of a Phase 3 study, including an estimate of effect size, headache variability, and desirable drug treatment start date.

Specific Aim 3 is to examine the feasibility of using headache diaries with individuals with mild TBI.

Specific Aim 4 is to establish the safety and tolerability of amitriptyline for the prevention of headache after mild TBI.

The investigators hypothesize that early preventive treatment with amitriptyline will avert the development of chronic post-traumatic headache (PTH) as compared to rates of headache from a recent natural history study on PTH after mild TBI.

The investigators propose to enroll inpatient subjects from a Level I trauma center as well as from outpatient clinics and from the general community with a diagnosis of mild TBI. Subjects will be screened for current headache. After baseline assessment, 72 subjects with current headache will be randomized to one of 2 groups. Group 1 will immediately begin amitriptyline and or Group 2 will be followed and begin amitriptyline at Day 30. All subjects will be asked to complete a daily headache diary beginning on Day 1 of the study. A detailed medical history and headache survey will be completed. Subjects will have a scheduled stepped increase in the drug dosage every week for 3 weeks to the maximum study dosage of 50 mg. Weekly telephone calls will monitor for adverse events and compliance with the drug and headache diary. Clinic visits will occur at 30, 60 and 90 days. The 30 day clinic visit will include cognitive testing to assess for differences between groups and initiation of drug treatment for Group 2. Both 30 and 60 day visits will include review of headache diary, potential adverse effects, and pill counts. The 90 day visit will be for outcome assessment. In addition, the headache survey will be repeated by telephone at Day 180.

Frequency and severity of headaches [ Time Frame: 90 days ] [ Designated as safety issue: No ]

Headache frequency and severity are the most frequently used measures of medication efficacy in headache research. We will measure the number of headaches per week and severity ratings (1-10)using headache diaries and report to research staff.

The HIT-6 is a well-developed brief measure of the effect headaches are having on patients, that is, a headache disability scale.72, 73 This 6 item test has excellent reliability and validity, including construct validity.

The SF-12 was originally developed in 1994 as a shorter alternative to the SF-36. The SF-36 is a well validated, widely used general health related quality of life measure.

Number of participants with adverse events [ Time Frame: Day 1 through Day 90 ] [ Designated as safety issue: Yes ]

The number and types of adverse events will be monitored on a weekly basis and will be divided into likelihood of association with the drug and into severity classes.

Headache characteristic survey [ Time Frame: Day 1, Day 30, Day 60, Day 90, Day 180 ] [ Designated as safety issue: No ]

This survey will gather information on several factors that will be used to comprehensively describe PTH and its treatment including International Classification of Headache Disorders, 2nd edition (ICHD) criteria (type of headache by characteristics such as location, duration, severity, associated symptoms.

This is a brief self-report of the person's subjective evaluation of insomnia. It targets the subject symptoms of insomnia as well as the concern or impact of the symptoms. This includes sleep onset and maintenance, satisfaction with current sleep pattern, interference with daily functioning, impairment and distress or concern.

The PHQ-9 will be used to assess depression. We are including this to measure any antidepressant effect of amitriptyline which was first used for this purpose. The nine items on the measure correspond with Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for depression, with each item scored from "not at all" to "nearly every day".

The Amitriptyline Immediate group will begin study drug immediately after enrollment. Immediate Drug participants will be started on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.

Drug: Amitriptyline

Participants with headache will be enrolled within the first 12 weeks after injury and will be randomly assigned to 2 groups (see Table 1 for summary of protocol). Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when they will receive their initial ramp-up dosage containers; see Table 2 for dosing), Day 30 and Day 60 (to monitor compliance and distribute study drug), and for final outcome on Day 90. Group 2 will be assessed within 3 months of injury (baseline, Day 0) but will not receive medication until their Day 30 visit. Those in group 2 who report headache at Day 30 will receive their initial dosage container and will then be reassessed at Day 60 (to monitor compliance and distribute study drug) and Day 90 (final outcome).

Other Name: Elavil

Experimental: Amitriptyline Delayed

The Amitriptyline Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.

Drug: Amitriptyline

Participants with headache will be enrolled within the first 12 weeks after injury and will be randomly assigned to 2 groups (see Table 1 for summary of protocol). Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when they will receive their initial ramp-up dosage containers; see Table 2 for dosing), Day 30 and Day 60 (to monitor compliance and distribute study drug), and for final outcome on Day 90. Group 2 will be assessed within 3 months of injury (baseline, Day 0) but will not receive medication until their Day 30 visit. Those in group 2 who report headache at Day 30 will receive their initial dosage container and will then be reassessed at Day 60 (to monitor compliance and distribute study drug) and Day 90 (final outcome).

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01856270